{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:29:42Z","timestamp":1792704582502,"version":"4.5.0"},"reference-count":54,"publisher":"Elsevier BV","issue":"2","license":[{"start":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T00:00:00Z","timestamp":1604188800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T00:00:00Z","timestamp":1604188800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["jpet.aspetjournals.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"published-print":{"date-parts":[[2020,11]]},"DOI":"10.1124\/jpet.120.000164","type":"journal-article","created":{"date-parts":[[2020,8,29]],"date-time":"2020-08-29T17:35:12Z","timestamp":1598722512000},"page":"376-384","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":19,"title":["Association Between N-Desmethylclozapine and Clozapine-Induced Sialorrhea: Involvement of Increased Nocturnal Salivary Secretion via Muscarinic Receptors by N-Desmethylclozapine"],"prefix":"10.1016","volume":"375","author":[{"given":"Shuhei","family":"Ishikawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Mikami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Tanimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuya","family":"Narumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Furugen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Kusumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Iseki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1124\/jpet.120.000164_bib1","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1097\/00004714-200112000-00012","article-title":"Therapeutic effect of pirenzepine for clozapine-induced hypersalivation: a randomized, double-blind, placebo-controlled, cross-over study","volume":"21","author":"Bai","year":"2001","journal-title":"J Clin Psychopharmacol"},{"key":"10.1124\/jpet.120.000164_bib2","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1016\/0006-3223(95)00296-0","article-title":"Salivary flow-rate and composition in schizophrenic patients on clozapine: subjective reports and laboratory data","volume":"39","author":"Ben-Aryeh","year":"1996","journal-title":"Biol Psychiatry"},{"key":"10.1124\/jpet.120.000164_bib3","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1345\/aph.1P761","article-title":"Current treatment strategies for clozapine-induced sialorrhea","volume":"45","author":"Bird","year":"2011","journal-title":"Ann Pharmacother"},{"key":"10.1124\/jpet.120.000164_bib4","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1038\/bjp.2008.355","article-title":"Central muscarinic receptor subtypes involved in pilocarpine-induced salivation, hypertension and water intake","volume":"155","author":"Borella","year":"2008","journal-title":"Br J Pharmacol"},{"key":"10.1124\/jpet.120.000164_bib5","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1046\/j.1460-9568.2003.02588.x","article-title":"Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine-induced seizure activity","volume":"17","author":"Bymaster","year":"2003","journal-title":"Eur J Neurosci"},{"key":"10.1124\/jpet.120.000164_bib6","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1037\/0033-2909.112.1.155","article-title":"A power primer","volume":"112","author":"Cohen","year":"1992","journal-title":"Psychol Bull"},{"key":"10.1124\/jpet.120.000164_bib7","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1172\/JCI109667","article-title":"Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects","volume":"65","author":"Dent","year":"1980","journal-title":"J Clin Invest"},{"key":"10.1124\/jpet.120.000164_bib8","doi-asserted-by":"crossref","first-page":"e90","DOI":"10.1111\/odi.12139","article-title":"Parasympathetic vasoactive intestinal peptide (VIP): a likely contributor to clozapine-induced sialorrhoea","volume":"20","author":"Ekstr\u00f6m","year":"2014","journal-title":"Oral Dis"},{"key":"10.1124\/jpet.120.000164_bib9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-0722.2009.00696.x","article-title":"N-Desmethylclozapine exerts dual and opposite effects on salivary secretion in the rat","volume":"118","author":"Ekstr\u00f6m","year":"2010","journal-title":"Eur J Oral Sci"},{"key":"10.1124\/jpet.120.000164_bib10","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1177\/0022034509356055","article-title":"Clozapine: agonistic and antagonistic salivary secretory actions","volume":"89","author":"Ekstr\u00f6m","year":"2010","journal-title":"J Dent Res"},{"key":"10.1124\/jpet.120.000164_bib11","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3758\/BF03193146","article-title":"G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences","volume":"39","author":"Faul","year":"2007","journal-title":"Behav Res Methods"},{"key":"10.1124\/jpet.120.000164_bib12","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1358\/dot.2005.41.6.893628","article-title":"Drug-induced sialorrhea","volume":"41","author":"Freudenreich","year":"2005","journal-title":"Drugs Today (Barc)"},{"key":"10.1124\/jpet.120.000164_bib13","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1111\/j.1600-0722.2011.00832.x","article-title":"Clozapine-induced salivation: interaction with N-desmethylclozapine and amisulpride in an experimental rat model","volume":"119","author":"Godoy","year":"2011","journal-title":"Eur J Oral Sci"},{"key":"10.1124\/jpet.120.000164_bib14","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1111\/j.1601-0825.2012.01926.x","article-title":"Atypical antipsychotics--effects of amisulpride on salivary secretion and on clozapine-induced sialorrhea","volume":"18","author":"Godoy","year":"2012","journal-title":"Oral Dis"},{"key":"10.1124\/jpet.120.000164_bib15","doi-asserted-by":"crossref","first-page":"S38","DOI":"10.1007\/BF00442557","article-title":"Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age","volume":"99","author":"Haring","year":"1989","journal-title":"Psychopharmacology (Berl)"},{"key":"10.1124\/jpet.120.000164_bib16","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1055\/s-0043-116492","article-title":"Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017","volume":"51","author":"Hiemke","year":"2018","journal-title":"Pharmacopsychiatry"},{"key":"10.1124\/jpet.120.000164_bib17","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1124\/jpet.115.225763","article-title":"The drug-drug effects of rhein on the pharmacokinetics and pharmacodynamics of clozapine in rat brain extracellular fluid by in vivo microdialysis","volume":"355","author":"Hou","year":"2015","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1124\/jpet.120.000164_bib18","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.psym.2017.08.011","article-title":"Clozapine-associated aspiration pneumonia: case series and review of the literature","volume":"59","author":"Kaplan","year":"2018","journal-title":"Psychosomatics"},{"key":"10.1124\/jpet.120.000164_bib19","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.ajp.2012.10.007","article-title":"Efficacy and tolerability of clozapine in Japanese patients with treatment-resistant schizophrenia: results from a 12-week, flexible dose study using raters masked to antipsychotic choice","volume":"6","author":"Kishi","year":"2013","journal-title":"Asian J Psychiatr"},{"key":"10.1124\/jpet.120.000164_bib20","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/0003-9969(65)90060-9","article-title":"The frequency of deglutition in man","volume":"10","author":"Lear","year":"1965","journal-title":"Arch Oral Biol"},{"key":"10.1124\/jpet.120.000164_bib21","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(13)60733-3","article-title":"Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis","volume":"382","author":"Leucht","year":"2013","journal-title":"Lancet"},{"key":"10.1124\/jpet.120.000164_bib22","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.schres.2010.02.1060","article-title":"Comparison of the efficacy and impact on cognition of glycopyrrolate and biperiden for clozapine-induced sialorrhea in schizophrenic patients: a randomized, double-blind, crossover study","volume":"119","author":"Liang","year":"2010","journal-title":"Schizophr Res"},{"key":"10.1124\/jpet.120.000164_bib23","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/0013-4694(75)90267-9","article-title":"The pattern of swallowing during sleep","volume":"38","author":"Lichter","year":"1975","journal-title":"Electroencephalogr Clin Neurophysiol"},{"key":"10.1124\/jpet.120.000164_bib24","doi-asserted-by":"crossref","first-page":"C1454","DOI":"10.1152\/ajpcell.00151.2007","article-title":"Distinct pathways of ERK activation by the muscarinic agonists pilocarpine and carbachol in a human salivary cell line","volume":"294","author":"Lin","year":"2008","journal-title":"Am J Physiol Cell Physiol"},{"key":"10.1124\/jpet.120.000164_bib25","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1111\/odi.12209","article-title":"The antipsychotic amisulpride: ultrastructural evidence of its secretory activity in salivary glands","volume":"20","author":"Loy","year":"2014","journal-title":"Oral Dis"},{"key":"10.1124\/jpet.120.000164_bib26","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1097\/00004714-199408000-00012","article-title":"Esophageal dysfunction in two patients after clozapine treatment","volume":"14","author":"McCarthy","year":"1994","journal-title":"J Clin Psychopharmacol"},{"key":"10.1124\/jpet.120.000164_bib27","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.ebiom.2017.11.030","article-title":"Steady-state clozapine and norclozapine pharmacokinetics in Maori and European patients","volume":"27","author":"Menkes","year":"2018","journal-title":"EBioMedicine"},{"key":"10.1124\/jpet.120.000164_bib28","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1016\/j.bbrc.2018.06.125","article-title":"Benefits of long-term pilocarpine due to increased muscarinic acetylcholine receptor 3 in salivary glands","volume":"503","author":"Minagi","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"10.1124\/jpet.120.000164_bib29","first-page":"119","article-title":"Drug-induced sialorrhoea and excessive saliva accumulation","volume":"18","author":"Miranda-Rius","year":"2009","journal-title":"Prescrire Int"},{"key":"10.1124\/jpet.120.000164_bib30","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1113\/jphysiol.2004.064626","article-title":"M3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice","volume":"558","author":"Nakamura","year":"2004","journal-title":"J Physiol"},{"key":"10.1124\/jpet.120.000164_bib31","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1113\/EP085110","article-title":"Partial agonistic effects of pilocarpine on Ca2+ responses and salivary secretion in the submandibular glands of live animals","volume":"100","author":"Nezu","year":"2015","journal-title":"Exp Physiol"},{"key":"10.1124\/jpet.120.000164_bib32","doi-asserted-by":"crossref","first-page":"284","DOI":"10.2330\/joralbiosci1965.39.284","article-title":"The paradoxical effects of the dibenzodiazepine derivative, clozapine, on autonomic stimulating drug-induced salivary responses in mice","volume":"39","author":"Ogawa","year":"1997","journal-title":"Jpn J Oral Biol"},{"key":"10.1124\/jpet.120.000164_bib33","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S0278-5846(01)00291-3","article-title":"Clozapine, norclozapine plasma levels, their sum and ratio in 50 psychotic patients: influence of patient-related variables","volume":"26","author":"Palego","year":"2002","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"10.1124\/jpet.120.000164_bib34","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1097\/00004714-199408000-00013","article-title":"Clozapine, nocturnal sialorrhea, and choking","volume":"14","author":"Pearlman","year":"1994","journal-title":"J Clin Psychopharmacol"},{"key":"10.1124\/jpet.120.000164_bib35","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1111\/joor.12664","article-title":"Salivary secretion in health and disease","volume":"45","author":"Pedersen","year":"2018","journal-title":"J Oral Rehabil"},{"key":"10.1124\/jpet.120.000164_bib36","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S0006-3223(97)00531-3","article-title":"Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram","volume":"44","author":"Perry","year":"1998","journal-title":"Biol Psychiatry"},{"key":"10.1124\/jpet.120.000164_bib37","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/S0143-4160(03)00149-0","article-title":"Regulation by clozapine of calcium handling by rat submandibular acinar cells","volume":"34","author":"Pochet","year":"2003","journal-title":"Cell Calcium"},{"key":"10.1124\/jpet.120.000164_bib38","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1097\/WNF.0b013e3181e204e0","article-title":"Salivary flow rate in patients with schizophrenia on clozapine","volume":"33","author":"Praharaj","year":"2010","journal-title":"Clin Neuropharmacol"},{"key":"10.1124\/jpet.120.000164_bib39","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/prd.12116","article-title":"The physiology of salivary secretion","volume":"70","author":"Proctor","year":"2016","journal-title":"Periodontol 2000"},{"key":"10.1124\/jpet.120.000164_bib40","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/S0006-3223(96)89255-9","article-title":"The effect of clozapine on saliva flow rate: a pilot study","volume":"40","author":"Rabinowitz","year":"1996","journal-title":"Biol Psychiatry"},{"key":"10.1124\/jpet.120.000164_bib41","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1176\/appi.ajp.2015.14050673","article-title":"Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine","volume":"172","author":"Rajji","year":"2015","journal-title":"Am J Psychiatry"},{"key":"10.1124\/jpet.120.000164_bib42","doi-asserted-by":"crossref","first-page":"97","DOI":"10.2165\/00044011-199917020-00003","article-title":"Comparative efficacy and tolerability of benzatropine and terazosin in the treatment of hypersalivation secondary to clozapine","volume":"17","author":"Reinstein","year":"1999","journal-title":"Clin Drug Investig"},{"key":"10.1124\/jpet.120.000164_bib43","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1080\/09243860412331282174","article-title":"Serous and mucous cells of human submandibular salivary gland stimulated in vitro by isoproterenol, carbachol and clozapine: an LM, TEM, and HRSEM Study","volume":"41","author":"Riva","year":"2003","journal-title":"Eur J Morphol"},{"key":"10.1124\/jpet.120.000164_bib44","doi-asserted-by":"crossref","first-page":"170","DOI":"10.3371\/CSRP.SAFI.061213","article-title":"Aspiration pneumonia due to clozapine-induced sialorrhea","volume":"9","author":"Saenger","year":"2016","journal-title":"Clin Schizophr Relat Psychoses"},{"key":"10.1124\/jpet.120.000164_bib45","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1177\/070674370705200607","article-title":"Clozapine-induced hypersalivation: a review of treatment strategies","volume":"52","author":"Sockalingam","year":"2007","journal-title":"Can J Psychiatry"},{"key":"10.1124\/jpet.120.000164_bib46","doi-asserted-by":"crossref","first-page":"109","DOI":"10.9758\/cpn.2015.13.1.109","article-title":"Effect of scopolamine butylbromide on clozapine-induced hypersalivation in schizophrenic patients: a case series","volume":"13","author":"Takeuchi","year":"2015","journal-title":"Clin Psychopharmacol Neurosci"},{"key":"10.1124\/jpet.120.000164_bib47","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s00441-005-0149-1","article-title":"Cytomorphological study on human submandibular gland following treatment with secretagogue drugs","volume":"324","author":"Testa Riva","year":"2006","journal-title":"Cell Tissue Res"},{"key":"10.1124\/jpet.120.000164_bib48","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1053\/smrv.2001.0183","article-title":"The significance of saliva during sleep and the relevance of oromotor movements","volume":"6","author":"Thie","year":"2002","journal-title":"Sleep Med Rev"},{"key":"10.1124\/jpet.120.000164_bib49","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.12740\/PP\/65307","article-title":"Therapeutic drug monitoring of atypical antipsychotics","volume":"51","author":"Urban","year":"2017","journal-title":"Psychiatr Pol"},{"key":"10.1124\/jpet.120.000164_bib50","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s00213-004-1940-5","article-title":"The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine","volume":"177","author":"Weiner","year":"2004","journal-title":"Psychopharmacology (Berl)"},{"key":"10.1124\/jpet.120.000164_bib51","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1007\/s00702-016-1573-y","article-title":"Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice","volume":"123","author":"Wohkittel","year":"2016","journal-title":"J Neural Transm (Vienna)"},{"key":"10.1124\/jpet.120.000164_bib52","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s00216-011-4831-8","article-title":"Sensitive quantification of clozapine and its main metabolites norclozapine and clozapine-N-oxide in serum and urine using LC-MS\/MS after simple liquid-liquid extraction work-up","volume":"400","author":"Wohlfarth","year":"2011","journal-title":"Anal Bioanal Chem"},{"key":"10.1124\/jpet.120.000164_bib53","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3164\/jcbn.10-31","article-title":"Evaluation of therapeutic effects of astaxanthin on impairments in salivary secretion","volume":"47","author":"Yamada","year":"2010","journal-title":"J Clin Biochem Nutr"},{"key":"10.1124\/jpet.120.000164_bib54","doi-asserted-by":"crossref","first-page":"203","DOI":"10.5834\/jdh.35.203","article-title":"Study on salivary secretion in organophosphorus poisoning: relation to cholinesterase inhibition in blood and organs of rats","volume":"35","author":"Yamanaka","year":"1985","journal-title":"J Dent Health"}],"container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356524269895?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356524269895?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1124\/jpet.120.000164","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T11:34:43Z","timestamp":1739964883000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0022356524269895"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11]]},"references-count":54,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,11]]}},"alternative-id":["S0022356524269895"],"URL":"https:\/\/doi.org\/10.1124\/jpet.120.000164","relation":{},"ISSN":["0022-3565"],"issn-type":[{"value":"0022-3565","type":"print"}],"subject":[],"published":{"date-parts":[[2020,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Association Between N-Desmethylclozapine and Clozapine-Induced Sialorrhea: Involvement of Increased Nocturnal Salivary Secretion via Muscarinic Receptors by N-Desmethylclozapine","name":"articletitle","label":"Article Title"},{"value":"The Journal of Pharmacology and Experimental Therapeutics","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1124\/jpet.120.000164","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2020 by The American Society for Pharmacology and Experimental Therapeutics","name":"copyright","label":"Copyright"}]}}